Liquid formulation comprising nicotine for aerosol administration

ABSTRACT

In one aspect, the present invention features a method of administering nicotine or a salt thereof to a human, wherein the method includes inhaling an aerosol of a liquid formulation, the liquid formulation comprising: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of said nicotine or a salt thereof; wherein the liquid formulation includes no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol. The present invention also features an aerosol-generating device and a reservoir for such a device containing such a liquid formulation.

This application is the national stage filing under 35 USC 371 of international application PCT/EP2015/061036 filed on May 20, 2015, which claims priority to SE 1450609-1 filed on May 21, 2014, the complete disclosures of which are hereby incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION

Over the years, various types of products have been developed, as an alternative means to smoking, to administer nicotine to a user to aid in smoking cessation (e.g., gums, lozenges, patches, nasal sprays, mouth sprays, and inhalators). For certain drugs, inhalation is considered as an efficacious route of administration due to the rapid absorption of the drug and avoidance of the first pass effect. For such drugs, a high plasma level can be achieved rapidly after inhalation of aerosol formulations. In the case of nicotine replacement therapy, it is believed that a rapid and sufficiently high nicotine plasma levels in the body is of high importance as tobacco smoking also delivers nicotine to the body in the form of inhalable aerosols.

Recently, e-cigarettes, electronic inhalators designed to look like a cigarette that generates aerosols usually containing nicotine, have become popular. These devices mimic the look and feel of a cigarette, but claim to avoid the dangers associated with inhaling burned tobacco smoke. In order to mimic cigarette smoke, these electronic inhalers often utilize liquid formulations (often containing glycerol) that, upon use, create aerosols that, like tobacco smoke, are visible upon exhalation by the user.

Although, many e-cigarettes formulations contain nicotine, their use as a means to quit smoking can be inadequate for various reasons, such as: (i) the nicotine concentration in the formulation can be too low, (ii) a considerable amount of nicotine can be lost by not being captured by the body, and (iii) given the visible aerosol they often generate, their use is not discreet and mimics the habit that the user desires to quit. Thus, there is a need to develop liquid formulation containing a high concentration of nicotine whose generated aerosol is less visible and is better retained in the oral and respiratory tracts.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a method of administering nicotine or a salt thereof to a human, wherein the method includes inhaling an aerosol of a liquid formulation, the liquid formulation comprising: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of said nicotine or a salt thereof; wherein the liquid formulation includes no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol.

In another aspect, the present invention features an aerosol-generating device comprising a reservoir containing a liquid formulation, wherein the liquid formulation comprising: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of said nicotine or a salt thereof; wherein the liquid formulation includes no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol and wherein the aerosol-generating device is arranged and configured to generate an aerosol of said liquid formulation.

In still another aspect, the present invention features a reservoir containing a liquid formulation, wherein the liquid formulation comprising: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of said nicotine or a salt thereof; wherein the liquid formulation includes no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol and wherein the reservoir is arranged and configured to attach to an aerosol-generating device to provide fluid communication for such liquid formulation from the reservoir to the aerosol-generating device.

Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon the description herein, utilizes the present invention to its fullest extent. The following specific embodiments can be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. As used herein, all percentages are by weight unless otherwise specified.

Liquid Formulation

As discussed above, the liquid formulation includes at least 12 percent by weight of water, at least 70 percent by weight of propylene glycol; and at least 2 percent by weight of nicotine or a salt thereof. In one embodiment, the liquid formulation contains at least 15 percent by weight of water, such as at least 20 percent by weight of water. In one embodiment, the liquid formulation contains up to 28 percent by weight of water, such as up to 25 percent by weight of water, such as up to 20 percent by weight water. In one embodiment, the liquid formulation contains at least 75 percent by weight of propylene glycol, such as at least 80 percent by weight of propylene glycol. In one embodiment, the liquid formulation contains up to 86 percent by weight of propylene glycol, such as up to 80 percent by weight of propylene glycol, such as up to 75 percent by weight propylene glycol. In one embodiment, the liquid formulation includes from 15 to 25 percent by weight of water, from 70 to 80 percent by weight of propylene glycol; and from 2 to 10 percent by weight of nicotine or a salt thereof.

Further, the liquid formulation includes no more than 5 percent by weight by weight of glycerol, such as no more than 1 percent by weight of glycerol, such as including no glycerol. As discussed above, the presence of glycerol in the formulation will result in a more visible aerosol form of the liquid formulation. Further, glycerol has a higher boiling point than propylene glycol, which would thus potentially raise the boiling point of the liquid formulation. Still further, glycerol can crystalize at low temperatures.

Still further, the liquid formulation includes no more than 5 percent by weight of ethanol, such as no more than 1 percent by weight of ethanol, such as including no ethanol. The inclusion of ethanol is not desired because of both the risk of separation due to rapid evaporation when heating the formulation to create an aerosol as well as the desire of certain users to avoid the intake of ethanol into their body.

As discussed above, the liquid formulation includes at least 12 percent by weight of water (e.g., from 12 to 28 percent water). As discussed below in the examples, Applicants have found that such a concentration of water lowers the boiling point of the liquid formulation while still maintaining at an acceptably low water activity to inhibit microbial activity (e.g., a water activity of less than 0.6). In one embodiment, the boiling point of the liquid formulation is less than 125° C., such as from 105° C. to 125° C. (e.g., when measured using the method recited in the European Pharmacopoeia 8^(th) Edition 2.2.12).

Maintaining the boiling point above 105° C. (e.g., by maintaining at least 70 percent by weight of propylene glycol) but below 125° C. not only allows for the creation of the aerosol at a temperature less than the temperature needed to create an aerosol with just propylene glycol and/or glycerol, but it also may help prevent the fractionation of water and propylene glycol during such process which may help maintain a uniform nicotine concentration within the resulting aerosol.

In one embodiment, the viscosity of the liquid formulation is less than 75 mPa·s, such as less than 50 mPa·s, such as less than 30 mPa·s (e.g., when measured using the method recited in the European Pharmacopoeia 8^(th) Edition 2.2.8 at 20° C.).

In one embodiment, the liquid formulation is manufactured by simple mixing of all the ingredients. Liquid ingredients are generally miscible with each other, while any solid ingredients may need to be dissolved in the mixture. Gentle heating of the constituent can help to dissolve solid components more rapidly.

Nicotine

The liquid formulation contains at least 2 percent by weight of nicotine or a salt thereof. In one embodiment, the liquid formulation includes nicotine (i.e., the free base of nicotine). In one embodiment, the liquid formulation includes a salt of nicotine. Examples of nicotine salts include, but are not limited to, formic (2:1), acetic (3:1), propionic (3:1), butyric (3:1), 2-methylbutyric (3:1), 3-methylbutynic (3:1), valeric (3:1), lauric (3:1), palmitic (3:1), tartaric (1:1) and (2:1), citric (2:1), malic (2:1), oxalic (2:1), benzoic (1:1), gentisic (1:1), gallic (1:1), phenylacetic (3:1), salicylic (1:1), phthalic (1:1), picric (2:1), sulfosalicylic (1:1), tannic (1:5), pectic (1:3), alginic (1:2), hydrochloric (2:1), chloroplatinic (1:1), silcotungstic (1:1), pyruvic (2:1), glutamic (1:1), and aspartic (1:1) salts of nicotine. While the use of the free base of nicotine is generally preferred, the use of such salts may be desirable to lower the pH to potentially reduce irritation for liquid formulations containing a high concentration of nicotine.

As discussed above, the liquid formulation contains at least 2 percent by weight of nicotine or a salt thereof, such as from 2 to 10 percent, such as 3 to 8 percent by weight of nicotine or a salt thereof. In one embodiment, the liquid formulation contains at least 3 percent by weight (e.g., 3-8 percent by weight), such as at least 4 percent by weight (e.g., 4-8 percent by weight), such as at least 5 percent by weight (e.g., 5-8 percent by weight) of nicotine or a salt thereof. Benefits of such a high concentration of nicotine include reducing the amount of vapor needed to deliver a specified amount of nicotine and reducing the number of inhalations needed to release the dose.

Aerosol-Generating Device

Numerous commercially available aerosol-generating devices have been developed to administer a liquid formulation as an aerosol to a user. In one embodiment, the aerosol-generating device is disposable after the liquid formulation stored within a reservoir within the device is exhausted. See, e.g., Njoy® King electronic cigarettes (Njoy, Scottsdale, Ariz.) and Vype™ (CN Creative, Manchester, England). In one embodiment, the aerosol-generating device comprises a reservoir for the liquid formulation that is replaceable once the liquid formulation is exhausted. See, e.g., Vuse™ digital vapor cigarettes (RJ Reynolds Vapor Company, Winston-Salem, N.C.) and Vype™ Reload (CN Creative, Manchester, England) and US Patent No. 2013/0192617. In one embodiment, the aerosol-generating device thermally creates the aerosol. See, e.g., US Patent Nos. 2014/0000638 and 2013/0192617 and European Patent No. 1618803. In one embodiment, the aerosol-generating device creates the aerosol through mechanical formation, such as a nebulizer (e.g., ultrasonic and pneumatic nebulizers such has disclosed in U.S. Pat. No. 8,127,772).

Optical Density of Aerosol

The optical density of the aerosol may be determined using the method of Example 5 of this application (“Optical Density”). In one embodiment, the Optical Density of the aerosol is less than 0.05, such as less than 0.025, such as less than 0.01, such as less than 0.005, such as less than 0.001 where such Optical Density is measured at 5, 10, 15, and/or 20 seconds. In one embodiment, the Optical Density of the aerosol is less than 0.01 at 10 seconds, such as less than 0.005 at 5 seconds, such as less than 0.005 at 10 seconds, such as less than 0.005 at 5 seconds.

Use of Aerosol of Liquid Formulation

In one embodiment, the method, reservoir, and/or device of the present invention is used as an aid to smoking cessation, including but not limited to reliving and/or preventing withdrawal symptoms and/or reducing smoking cravings (e.g., for a user that is trying to stop smoking or reduce the number of cigarettes smoked). In one embodiment, the method includes the administration of from about 0.01 mg to about 0.25 mg of nicotine per inhalation (e.g., the device utilizing the liquid formulation is arranged and configured to generate an aerosol of the liquid formulation containing from about 0.05 mg to about 0.15 mg of nicotine per inhalation.

EXAMPLES

Specific embodiments of the present invention are illustrated by way of the following examples. This invention is not confined to the specific limitations set forth in these examples.

Example 1 Measurement of Boiling Point

Various liquid formulations including nicotine, water, and/or propylene glycol are set-forth below in Table 1. These examples were manufactured as follows. First, all the ingredients were weighed. The Nicotine free base was added to the water, and then propylene glycol was added to nicotine/water solution followed by simple mixing to obtain homogenous liquid formulation. The boiling points for each of the formulations were measured and are recorded in Table 1.

TABLE 1 Propylene Glycol Water Nicotine Boiling Point (w/w %) (w/w %) (w/w %) (° C.)* Example 1A 100 0 0 188 Example 1B 97 0 3 147.2 Example 1C 89.1 9.9 1 122.4 Example 1D 90 10 0 121.7 Example 1E 77.6 19.6 2 116.0 Example 1F 58.8 39.2 2 108.5 Example 1G 39.2 58.8 2 105.6 Example 1H 19.6 77.6 2 102.0 Example 1I 0 98 2 99.2 *Boiling point was measured using the method described in the European Pharmacopoeia 8^(th) Edition 2.2.8

Thus, as indicated in Table 1, even the mere addition of 10% water reduced the boiling point of the liquid formulation from 188 to 121.7° C. Such a reduction allows the liquid formulation to form an aerosol at a much lower temperature.

Example 2 Water Activity

Water activity, or a_(w), is the partial vapor pressure of water in a substance divided by the standard state partial vapor pressure of water. Water activity is based on a scale of 0 to 1.0 with pure water having a water activity of 1.0. Usually products that contain lower percent moisture have lower water activity. Water activity is an important characteristic to determine the antimicrobial properties of the formulation. Since yeast, molds, and bacteria require a certain amount of available water to support growth, designing a formulation with a water activity below 0.6 provides an effective control against such growth.

Various liquid formulations including nicotine, water, and/or propylene glycol are set-forth below in Table 2. These examples were manufactured as set forth in Example 1. The water activity (a_(w)) of these formulations was measured using an AquaLab 4TEV (Pullman, Wash. USA) chilled mirror water activity instrument and recorded in Table 2.

TABLE 2 Propylene Glycol Water Nicotine Water (w/w %) (w/w %) (w/w %) Activity* Example 2A 100 0 0 0.18 Example 2B 89.1 9.9 1 0.44 Example 2C 87.3 9.7 3 0.43 Example 2D 78.4 19.6 2 0.57 Example 2E 68.6 29.4 2 0.69 Example 2F 58.8 39.2 2 0.77 Example 2G 88.2 9.8 2 0.35 Example 2H 78.4 19.6 2 0.54 Example 2I 68.6 29.4 2 0.66 Example 2J 58.8 39.2 2 0.74 Example 2K 86.4 9.6 4 0.35 Example 2L 76.8 19.2 4 0.54 Example 2M 67.2 28.8 4 0.67 Example 2N 57.6 38.4 4 0.75 *The water activity was measured by an AquaLab 4TEV apparatus. Formulations containing less than 20% w/w of water were able to maintain a water activity of less than 0.6. Further, as seen when comparing below Examples 2B and 2C, changing the concentration of nicotine from 1 to 3 percent did not have a significant effect on the water activity of the liquid formulation.

Example 3 Aerosol Visibility

Various liquid formulations including nicotine, water, and/or propylene glycol are set-forth below in Table 3. These examples were manufactured as set forth in Example 1.

TABLE 3 Composition w/w % Test results Pro- Water Boiling Formu- Nico- pylene Activ- Point Viscosity lations tine Water glycol ity* (° C.)** mPa.s*** Example 3.00 0.00 97.00 0.00 147.2 56,601 3A Example 4.50 0.00 95.50 0.00 151.7 61,101 3B Example 3.00 4.85 92.15 0.22 134.2 51,218 3C Example 4.50 4.78 90.73 0.21 125.6 47,637 3D Example 3.00 9.70 87.30 0.35 121.2 30,481 3E Example 4.50 9.55 85.95 0.35 126.4 41,132 3F Example 3.00 19.40 77.60 0.55 114.7 25,756 3G Example 4.50 19.10 76.40 0.55 111.8 22,392 3H Example 3.00 29.10 67.90 0.68 110.2 16,827 3I Example 4.50 28.65 66.85 0.68 108.5 14,301 3J Example 3.00 38.80 58.20 0.75 106.6 11,223 3K Example 4.50 38.20 57.30 0.76 105.1 10,827 3L Example 6 28.20 65.80 0.65 104.0 14,662 3M Example 6 18.80 75.20 0.53 106.6 21,160 3N Example 6 9.40 84.60 0.34 113.1 30,847 3O *The water activity was measured by an AquaLab 4TEV apparatus. **Boiling point was measured using the method described in the European Pharmacopoeia 8^(th) Edition 2.2.8 ***Viscosity was measured using the method described in the European Pharmacopoeia 8^(th) Edition 2.2.8 at 20° C.

These liquid formulations were tested with an aerosol-generating device composed of a cartomizer (Boge 510 Standard Resistance, Vaper Venue, Buena Park, Calif.) fitted to a battery (510 Titan Tank 340 mAh Mega Automatic Battery, Totally Wicked Blackburn Lancashire, United Kingdom). About 0.8 g of a formulation was filled into the liquid reservoir of the cartomizer, which was then fitted to the battery. The liquid formulations were tested for nicotine release using an in vitro puffing method. The aerosol generated by the device was captured and the nicotine level was determined. The result showed uniformity in nicotine release. For certain formulations in Table 3 more than 90% of the nicotine concentration of the formulation was measured in the captured aerosol.

All aerosols according to above Table 3 were less visible than the aerosols from a large number of commercial e-cigarettes. The aerosols according to Table 3 disappeared more rapidly upon dilution with the air. A slight additional decrease in aerosol visibility and duration was also noticed with increasing proportion of water in the formulations.

Example 4 Formulation Stability

The stability of Example 3N was followed during 12 weeks at three storage conditions: 25° C./60% RH (Table 4A), 40° C./75% RH (Table 4B), and 60° C. ambient % RH (Table 4C). A gradient ultra-high performance liquid chromatography (UHPLC) method using a C18 column withstanding high pH and acetonitrile/ammonium acetate buffer as the eluent with UV detection at 230 to 260 nm. The results show an acceptable stability under these storage conditions.

TABLE 4A Specification Storage time (weeks) Attributes Method Limits Units 0 4 8 12 Description¹ Visual Informative Clear Clear Clear Clear inspection solution solution solution solution Nicotine UHPLC Rt matches Rt Rt Rt Rt identity² standard matches matches matches matches standard standard standard standard Nicotine Assay⁵ UHPLC 54.0-66.0 mg/ml 61.7 61.4 62.7 62.5 Impurities^(3,5) Cotinine UHPLC Informative % l.c. n.d n.d n.d n.d Nicotine-cis-N- UHPLC Informative % l.c. n.d n.d n.d n.d oxide Nicotine-trans- UHPLC Informative % l.c. n.d n.d n.d n.d N-oxide Norcotinine UHPLC Informative % l.c. n.d n.d n.d n.d Nornicotine UHPLC Informative % l.c. 0.11 0.13 0.11 0.10 β-Nicotyrine UHPLC Informative % l.c. n.d n.d n.d n.d β-Nornicotyrine UHPLC Informative % l.c. n.d n.d n.d n.d Myosmine UHPLC Informative % l.c. n.d 0.05 0.07 0.07 MNP⁴ UHPLC Informative % l.c. n.d n.d 0.03 0.04 Any unspecified UHPLC Informative % l.c. n.d n.d n.d n.d Sum UHPLC Informative % l.c. 0.11 0.18 0.21 0.21 ¹Clear, colorless solution ²Conforms to test-retention time matches standard. ³No peaks smaller than the integration threshold (IT) are integrated, IT is defined as the area, which is 0.05% of the nicotine peak area (the average peak area of the system suitability solution for nicotine). Peaks below IT are reported as n.d. ⁴1-methyl-3-nicotinoylpyrrolidine ⁵“% l.c.” is the percent related substance of nicotine label claim, “n.a.” and “n.d.” stands for not analyzed and not detected, respectively

TABLE 4B Specification Storage time (weeks) Attributes Method Limits Units 0 4 8 12 Description¹ Visual Informative Clear Clear Clear Clear inspection solution solution solution solution Nicotine UHPLC Rt matches Rt Rt Rt Rt identity² standard matches matches matches matches standard standard standard standard Nicotine Assay⁵ UHPLC 54.0-66.0 mg/ml 61.7 62.0 62.5 61.8 Impurities^(3,5) Cotinine UHPLC Informative % l.c. n.d n.d n.d n.d Nicotine-cis-N- UHPLC Informative % l.c. n.d n.d 0.06 0.13 oxide Nicotine-trans- UHPLC Informative % l.c. n.d 0.09 0.14 0.25 N-oxide Norcotinine UHPLC Informative % l.c. n.d n.d n.d n.d Nornicotine UHPLC Informative % l.c. 0.11 0.13 0.10 0.12 β-Nicotyrine UHPLC Informative % l.c. n.d n.d n.d n.d β-Nornicotyrine UHPLC Informative % l.c. n.d n.d n.d n.d Myosmine UHPLC Informative % l.c. n.d 0.05 0.05 0.07 MNP⁴ UHPLC Informative % l.c. n.d 0.04 0.04 0.04 Any unspecified UHPLC Informative % l.c. n.d n.d n.d n.d Sum UHPLC Informative % l.c. 0.11 0.31 0.39 0.61 ¹Clear, colorless solution ²Conforms to test-retention time matches standard. ³No peaks smaller than the integration threshold (IT) are integrated, IT is defined as the area, which is 0.05% of the nicotine peak area (the average peak area of the system suitability solution for nicotine). Peaks below IT are reported as n.d. ⁴1-methyl-3-nicotinoylpyrrolidine ⁵“% l.c.” is the percent related substance of nicotine label claim, “n.a.” and “n.d.” stands for not analyzed and not detected, respectively

TABLE 4C Specification Storage time (weeks) Attributes Method limits Units 0 4 8 12 Description¹ Visual Informative Clear Clear Clear Clear inspection solution solution solution solution Nicotine UHPLC Rt matches Rt Rt Rt Rt identity² standard matches matches matches matches standard standard standard standard Nicotine Assay⁵ UHPLC 54.0-66.0 mg/ml 61.7 61.4 62.7 62.5 Impurities^(3,5) Cotinine UHPLC Informative % l.c. n.d n.d 0.04 0.07 Nicotine-cis-N- UHPLC Informative % l.c. n.d 0.21 0.46 0.74 oxide Nicotine-trans-N- UHPLC Informative % l.c. n.d 0.43 0.87 1.27 oxide Norcotinine UHPLC Informative % l.c. n.d n.d n.d n.d Nornicotine UHPLC Informative % l.c. 0.11 0.12 0.11 0.14 β-Nicotyrine UHPLC Informative % l.c. n.d n.d n.d n.d β-Nornicotyrine UHPLC Informative % l.c. n.d n.d n.d 0.02 Myosmine UHPLC Informative % l.c. n.d 0.07 0.08 0.09 MNP⁴ UHPLC Informative % l.c. n.d 0.07 0.07 0.10 Any unspecified UHPLC Informative % l.c. n.d n.d n.d 0.11 Sum UHPLC Informative % l.c. 0.11 0.90 1.63 2.54 ¹Clear, colorless solution ²Conforms to test-retention time matches standard. ³No peaks smaller than the integration threshold (IT) are integrated, IT is defined as the area, which is 0.05% of the nicotine peak area (the average peak area of the system suitability solution for nicotine). Peaks below IT are reported as n.d. ⁴1-methyl-3-nicotinoylpyrrolidine ⁵“% l.c.” is the percent related substance of nicotine label claim, “n.a.” and “n.d.” stands for not analyzed and not detected, respectively

Example 5 Optical Density of Aerosol

The optical densities of aerosols produced from two formulations of the present invention were compared to aerosols produced by five commercially-available, nicotine aerosol-generating devices. The optical density of the aerosol produced by these seven formulations was tested in an in vitro model. For this model, a four liter cylindrical chamber was constructed having a radius of 12.5 cm and the top and bottom constructed of clear polycarbonate to allow for the measurement of the optical density of the aerosol introduced into the chamber using a photometer (Hagner Photometer, Hagner Photometric Instruments Ltd., Havant, Sweden) positioned on one side of the chamber and a white light source positioned on the other side of the chamber. The chamber contains an aerosol introduction tube that forces air at a rate of 1 L/min for 3 seconds through the air inlet hole of the respective aerosol-generating devices and directs the resulting aerosol (50 ml of aerosol) into the chamber. The chamber further contains both a fan (a 50 mm fan running at approximately 2 CFM) to promote mixing and homogenization of introduced aerosol and a one way air check valve to both release any pressure increase within the chamber following introduction of the aerosol and allow flushing of the chamber in between each test.

For each device, the optical density was calculated using the following equation:

Optical Density=−log₁₀(I/I ₀) where I=light intensity and I ₀=initial light intensity

Measurements were taken for 20 seconds following first instruction of the aerosol into the chamber (i.e., for the 3 seconds that the aerosol was introduced and for the seventeen seconds afterwards). The results of the studies are set forth below in Table 5.

TABLE 5 Optical Density Formulation 5 sec 10 sec 15 sec 20 sec Example 3F¹ 0.002 0.000 0.002 0.002 Example 3J¹ 0.000 0.000 0.000 0.000 Vype ™ Classic Regular² 0.087 0.087 0.092 0.092 Vype ™ Classic Bold² 0.083 0.086 0.086 0.086 Njoy ™ King Gold³ 0.066 0.063 0.063 0.063 Njoy ™ King Bold³ 0.104 0.101 0.101 0.101 Vuse ™ Original⁴ 0.079 0.076 0.076 0.076 ¹Aerosols of Examples 3F and 3J were created with a Joyetech 510-T body (Joyetech USA Inc, Irvine, CA) with Boge 510 cartomizer ²Nicoventures Ltd., London, UK ³Njoy, Scottsdale, AZ ⁴RJ Reynolds Vapor, Salem, NC As is evident from the result in Table 5, Examples 3F and 3J produced unexpected, minimally persistent aerosols compared to tested commercial formulations. The Optical Density of Example 3F ranged between 0 and 0.002 while the Optical Density of Example 3J was 0 from 5-20 seconds. The five commercially available devices produced aerosols having much higher Optical Densities, ranging from 0.063 to 0.104 from 5-20 seconds.

It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims. 

What is claimed is:
 1. A method of administering nicotine or a salt thereof to a human, wherein said method comprises inhaling an aerosol of a liquid formulation, said liquid formulation comprising: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of said nicotine or a salt thereof; wherein said liquid formulation comprises no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol.
 2. A method of claim 1, wherein said liquid formulation does not comprise glycerol.
 3. A method of claim 1, wherein said liquid formulation does not comprise ethanol.
 4. A method of claim 1, wherein said liquid formulation comprises at least 15 percent by weight of water.
 5. A method of claim 1, wherein said liquid formulation comprises at least 75 percent by weight of propylene glycol.
 6. A method of claim 1, wherein said liquid formulation comprises nicotine.
 7. A method of claim 6, wherein said liquid formulation comprises at least 4 percent by weight of said nicotine.
 8. A method of claim 1, wherein the boiling point of said liquid formulation is less than 125° C.
 9. A method of claim 1, wherein the viscosity of the liquid formulation is less than 50 mPa·s.
 10. A method of claim 1, wherein said aerosol has an Optical Density of less than 0.01 at 10 seconds.
 11. An aerosol-generating device comprising a reservoir containing a liquid formulation, wherein said liquid formulation comprises: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of nicotine or a salt thereof; wherein said liquid formulation comprises no more than 5 percent by weight of glycerol and no more than 5 percent by weight of ethanol, and wherein said aerosol-generating device is arranged and configured to generate an aerosol of said liquid formulation.
 12. An aerosol-generating device of claim 11, wherein said liquid formulation does not comprise glycerol.
 13. An aerosol-generating device of claim 11, wherein said liquid formulation does not comprise ethanol.
 14. An aerosol-generating device of claim 11, wherein said liquid formulation comprises at least 15 percent by weight of water.
 15. An aerosol-generating device of claim 11, wherein said liquid formulation comprises nicotine.
 16. A reservoir containing a liquid formulation, wherein said liquid formulation comprises: (i) at least 12 percent by weight of water; (ii) at least 70 percent by weight of propylene glycol; and (iii) at least 2 percent by weight of nicotine or a salt thereof; wherein said liquid formulation comprises less than 5 percent by weight of glycerol and less than 5 percent by weight of ethanol; and wherein said reservoir is arranged and configured to attach to an aerosol-generating device to provide fluid communication for such liquid formulation from said reservoir to said aerosol generating device.
 17. A reservoir of claim 16, wherein said liquid formulation does not comprise glycerol.
 18. A reservoir of claim 16, wherein said liquid formulation does not comprise ethanol.
 19. A reservoir of claim 16, wherein said liquid formulation comprises at least 15 percent by weight of water.
 20. A reservoir of claim 16, wherein said liquid formulation comprises nicotine. 